Substituted sulfanilylsulfanilamides



Patented July 19, 1949 UNITED STATES PTNT OFFICE SUBSTITUTED SULFANILYL- SULFANILAMIDES Nqllrawing. Application July 5, 1943, Serial No. 493,579

10--Claims. 1

This. e tiv at N ar e r cy anilylsulfanilamides in which the carboxyacyl group is theradicalremaining when the hydroxyl group is. removed from onlyfone oi the two or more carboxyl groups of a heterocyclic polycarboxylicacid, and. the invention covers such products containing the remaining carboxyl group or groups unaltered as Well as with .the hydrogen in y of 1. rem in ne erboxyl.groups rep a d by a car x late-iormine.eIementprrau CaL The new products ofthisinvention are in general therapeutically useful in varying degrees and applications, for example, in treating ailments of the intestinal tract,

The products of this invention may be represented by the general formula in which M is selected from. hydrogenand monovalent and polyva lent radlcalscapable of. com bining with a. carboxyl radical to. form a carboxylate, such. as the alkali metals sodium, potassium, lithium. and the. like thealkaline earths as calcium, magnesium, barium and. the like, antimony, copper,'gold, iron bismuth, and manganese and the like; an alkyl radical, a nitrogen base as ammoniumandcorrespondingradicals of alkyl amines. and alkanolamlnes and the like; and R is thenresidue of ai-heterooyclic polycarboxylic acidfstripped of its carboxyl groups; and T is selected. -.frm -hydrogei i.and the M-monovalent radicals "and freewalences of; the M-polyvalent radicals not sat isfied by --the sing1e carbox 1 groupshown;directly 1ihkedto M; and n is 88-18 ted m e o ndenvi he eenumb up to four. whereby the grouping represents the, carboxyl' andathe carboxylate groups over two .from any polycarboxylic acid having more. than'two carboxylegroups, and m is a small number. selected irom.-the class consisting of (A). one, inithoselcompoundsz embraced herein in which all-orthe carboxyl groups in the carboxyacyl radical satisfy-allots. the valences of any polyvalent.radicals,represented-by M and T; and (B) a smallnumber equal tothe valences f M, in those mp unds: embraced herein and selected from those. (a)- in.which.n.-is zero, (b) in W ea Occu rence-cube.radi al Dis selected from .hydrogen and any ofie the.. .monovalent radicals represented by; {Maudie}; ln-which each occurrence of the radlcalT'isdifierent from the radical M; and E and G are each separately selected from hydrogen and. alkyl; .araikyl and aryl radicals.

The expression carboxylates used. in this specification and its appending claims embraces those groups resulting from replacing the hydrogen of a carboxyl group with any other group.- ing capable of combining with a carbioxyllradical to form a carboxylate such as-the various metals and the like, or an alkyl radical or anitrogen base and the like of the type. hereinabove 111115.- trated at column 1, lines 22 through 31, preparation of which is illustrated at column- 4', lines 25 through 49.

The carboxyacyl group (remaining group when the hydroxy group is removed from only one of the at least two carboxyl groups of a polycarboxylic acid) may be derived from anydesirable heterocyclic polycarboxylic acid, for example, the pyridine polycarboxylic acids as the dicarboxypyridines such as quinolinic acid (2,3-dicarboxypyridine), lutidinic acid (2,4-dicarboxypyridine), 2,5-dicarboxypyridine, cinchomeronic acid (3,4-dicarboxypyridine) dipicolinic acid (2,6-dicarboxypyridine), and dinicotinic acid. (3,5-dicarboxypyridine), also the diazine polycarboxylic acids as the dicarboxydiazines, for example, the dicarboxypyrazines, such as antipellagricacid (2,3-di carboxypyrazine) 2,5-dicarboxypyrazine and 2,$-. dicarboxypyrazine, as well as the derivatives thereof substituted on the nucleus, for example; those alkyl-substituted on the nucleus. as the homologs of antipellagric acid such as the. nu-.' clear-monoalkyl derivaties, as 2,3-dicarboxy-5 methyl-pyrazine, and the nuclear-di'alkyl' derivatives as 2,3-dicarboXy-5,6-dimethyl-pyrazine, as well as 2-carboxy-3-methyl-5-carboxy-6'- methyl pyrazine, and also dicarboxypyridazines such as 4,5-dicarboxypyridazine as well as the derivatives thereof substituted on thenucleus, such.

as those alkyl substituted on the nucleus as 4,5- dicarboxy-3,6-dimethyl-pyridazine, and also the dicarboxypyrimidines such as 4,5-dicarboxypyrimidine and 4,6-dicarboxypyrimidine. Also included are the thiazole polycarb'oxylic acids;

such as the dicarboxythiazoles; aswell as. the derivaties thereof substituted on the nucleus; such as 2-methyl-d,5-dicarboxythiazo1e.

Thus, in this specification and the appending claims the expression dicarboxydiazine. can.

only cover a member of the class ofthedicarboxypyridazines, dicarboxy-pyrimidines,: and; di carboxy-pyrazines, each of which 1 contains no substitutents other than the-twocarboxyl groups 3 on the diazine nucleus as well as these dicarboxydiazines further substituted on said diazine nucleus by one or two alkyl substituents as described above. Likewise, the expression dlcarboxythiazole embraces only the thiazole nucleus containing no substituents other than the two carboxyl groups and such dicarboxy-thiazole group further substituted on the thiazole nucleus by an alkyl radical as indicated above.

The invention also includes the preparationof these N carboxyacyl sulfanilylsulfanilamides which are made by heating the desired polycarboxylic acid, its anhydride or acid chloride such as the di-acid chloride thereof, with sulfanilylsulfanilamide, either merely together or in an inert reaction medium such as an inert solvent, and as in the latter case and with the acid chic-- ride separating the desired end product. 1

The invention may be illustrated by, but not restricted to, the following:

Example.-- N -cmt pellctgroyl-sulianilylsulfanilamide .-=i.3 grams of 2,3-dicarboxypyrazine anhydride is added in portions to a boiling suspen-.

sion of 9.4 grams of sulfanilylsulfanilamide in '75 cc. of alcohol. After the addition is completed, the mixture is boiled for five minutes to assure complete precipitation of the product and is then allowed to cool. The cooled mixture is then filtered and'the residue on the filtrate taken up with aqueous sodium bicarbonate solution dissolving the desired product and leaving an insoluble residue which is removed by filtration. The filtrate is then made just slightly acid with hydrochloric acid and the desired product'precipitated, filtered off and purified,,for example, byreprecipitation, is

nilylsulfanilamide, N cinchomeronoyl sulfanilylsulianilamide and N -(2-methyl-5-carboxythiazolel-carboxylyl) -sulfanilylsulfanilamide.

'By heating sulfanilylsulianilamide with approximately 2. 15% excess over an equimolecular portion of respectively lutidinlc acid, dinicotinic acid, and dipicolinic acid, in intimate mixture to a fusion temperature around between 160190 C. a

in a sand bath for about between an hour and an hour and a half with occasional manual stirring, then cooling the melt and taking it up in dilute alkali, around 5%, and precipitating with a slight excess of hydrogen chloride, and then filtering off the precipitate and treating it with cool sodium bicarbonate solution and filtering off the soluble residue,and then making this filtrate slightly acid with hydrogen chloride, there result the follow- 1 7 ing corresponding products, which may be further purified. by recrystallization with methyl Cellosolve and water: N -lutidinoyl-N -4-sulfamylphenylsulfanilamide, N -dinicotinoyl-NlA-sulfamylphenylsulfanilamide and N-dipicolinoyl- N -4-sulfamylphenylsulfanilamide.

By adding an equimolecular stoichiometric equivalent of sulfanilylsulfanilamide in small portions over a forty minute period to a solution of a given amount of the di-acid chloride of 4,6-dicarboxypyrimidine in a suitable quantity of a solvent such as dioxan (for example, .006 mol of each reactant in about 5O ccl of solvent) and permitting the mixture to stand at room temperature for about at least ten minutes after the addition is completed, and then pouring the mixture into a suitable quantity (approximately cc.) of dilute sodium bicarbonate solution, filtering oil the insoluble portion after the efiervescence discontinues, thenlclarifying the filtrate with charcoal and after the removal of the latter making-the filtrate acidwith hydrogen chloride andichilling it, there results 'N (6-carboxy-pyrimidinef4'-,car boxylyl)-N -4.sulfamylphenylsulfanilamide.

The ,carbo'xylate form of any of the compounds of the invention may be prepared, for example, by adding to a small amount of Waterfan excessof the compound over its solubility in water anddissolving the excess by stirring in a. sufiicient quantity of, for example, anhydrous sodiumcarbonate. The solution is preferably filtered and from the filtrate the highly soluble sodium salt can be isoe l-ated, for example, by adding an equal'volumeof alcohol and pouring the resulting solution'linto about, 10 volumes of acetone; Thesubs'tance thrown out'of solution is permitted to settle'and the supernatant liquid withdrawn and the residue preferably treated several times Withv fresh acetone. After decanting the acetone from the last treatment, the resulting desired sodium salt may be dried preferably under vacuum, 7

Other metalcarboxylate salts of the compound such as the copper, gold, iron and bismuth salts and the like may be obtained byreacting. the al kali metal salts, preferably in aqueous solution, with a suitable soluble salt of the metal, the car: boxylate salt oirwhic'h is desired. The desired care. boxylate saltis obtained by resulting'doubl'e dee composition. i I, Q

' The compounds of the invention, applicable in treating ailments of the intestinahtract, ex

hibit such activity by the introduction to. the;

various nuclear portions of the individual com; pound, of substituents, the introduction of which into the basic nucleus leaves the'compound substantially non-toxic so that it would cause no permanent injury to the subject when adminis-' tered in the necessaryth'erapeutic dosage. V The metallic element in the compounds used as in preparations for treatingintestinalailments are such that their inclusion in the compound introduces similarly no unduly toxic characteristics. Thus, for example, as with 'N -quinoli1ioyl-sulfanilylsulfanilamide, it is possible to build up a high concentration in. the intestinal tract with-f out 2. simultaneously high blood level."

The various compounds, used in the treatment of intestinal ailments are administered orally, either inthefo'rm of tablets, capsules or powders of the'solid'material, or as solutions of any suitable concentration thereof; v V While the compounds "constituting the invention' have been'desc'ribed byre'ference to certain specific embodiments thereof, other modifications, extensions of substitutions maybe made therein within the scope of the depending claims as limited by the state of the art.

What is claimed is: 1. N carboxyacylsulfanilylsulfanilamides the general formula in which R is a divalent heterocyclic radical with its carboxyl group and the carbonyl group shown in the general formula linked respectively to separate nuclear carbon atoms of a mononuclear heterocycle which is a member of the class consisting of (a) diazine, (b) thiazole, (c) pyridine, and (d) each of the heterocycles (a) and (b) alkyl-substituted elsewhere than at the heteroatom and the carbon atoms to which the carbonyl and the carboxyl groups are linked.

2. N carboxyacylsulfanilylsulfanilamides, as claimed in claim 1, wherein the only substituents on the heterocyclic radical are the carboxyl group and the carbonyl group shown in the general formula linked respectively to separate nuclear carbon atoms.

3. N carboxyacylsulfanilylsulfanilamides, as claimed in claim 1, wherein the heterocyclic radical R is alkyl-substituted.

4. N carboxyacylsulfanilylsulianilamides, as claimed in claim 1, wherein the heterocyclic radical is a diazine radical.

5. N carboxyacylsulfanilylsulfanilamides, as claimed in claim 1, wherein the heterocyclic radical is the diazine radical.

6. N carboxyacylsulfanilylsulfanilamides, as claimed in claim 1, wherein the heterocyclic radical is an alkyl-substituted diazine radical.

'7. N carboxyacylsulfanilylsulfanilamides, as

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Number Name Date 2,323,651 Dohrn July 6, 1943 3 Moore July 13, 1943 FOREIGN PATENTS Number Country Date 502,558 Great Britain Mar. 15, 1939 843,415 France Mar. 2'7, 1939 OTHER REFERENCES Journal Amer. Chem. Soc, March 1939, pp. 613-616.

Prac. Soc. Exper. Biol. and Med., Oct. 1941, page 129.

Chemical Reviews, Aug. 1940, pp. 121-125, lsggurnal Amer. chem. 500., July 1942, pp. 1572- 

